Copper Catalyzed Three-Component Ullmann C-S Coupling in PEG for the Synthesis of 6-Aryl/alkylthio-purines.

To tackle the environmental unfriendly issue in existing synthesis strategies for 6-substitued thiopurine derivatives, such as poor step economy, frequent use of malodorous organic sulfur starting materials, toxic organic solvents, and equivalent dosage of base, we have developed a CuI-catalyzed base-free three-component Ullmann C-S coupling synthetic strategy, featured using inorganic salt Na2S as the sulfur source and nontoxic PEG-600 as the solvent. The newly developed strategy is particularly effective for the synthesis of 6-arylthiopurines. The high catalytic efficiency in PEG-600 can be rationalized by the high soluble ability of CuI catalyst, likely due to the presence of multiple oxygen coordination sites in PEG.

Regulating CO and H2 Ratios in Syngas Produced from Photocatalytic CO2/H2O Reduction by Cu and Co Dual Active Centers on Carbon Nitride Hollow Nanospheres.

For photocatalytic CO2 reduction to produce syngas, there are challenges in achieving a high catalytic efficiency and precise control over the product ratio. In this study, two non-noble metal complexes Cobpy and Cubpy (bpy = 2,2'-bipyridine) as cocatalysts for CO2 reduction and hydrogen evolution, respectively, were in situ supported on carbon nitride hollow nanospheres to construct a hybrid system for photocatalytic syngas production. The resulting CO/H2 ratio can be precisely regulated within a wide range of 0:1-9:1 by accurately controlling the content of the two complexes. The presence of the two complexes promotes the migration of photogenerated electrons of the carbon nitride. CO2 can be reduced to CO on the photoreduced species Co(bpy)2+ of Cobpy on CNHS, and H+ can be reduced to H2 on the photoreduced species Cu(bpy)2+ of Cubpy. Furthermore, this method is also applicable to other photocatalysts, such as CdS and TiO2 for generating syngas and regulating product ratios.

A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters.

The palladium-catalyzed Sonogashira coupling of α, ß-unsaturated acid derivatives offers a diversity-oriented synthetic strategy for cross-conjugated enynones. However, the susceptibility of the unsaturated C-C bonds adjacent to the carbonyl group toward Pd catalysts makes the direct conversion of α, ß-unsaturated derivatives as acyl electrophiles to cross-conjugated ketones rare. This work presents a highly selective C-O activation approach to prepare cross-conjugated enynones using α, ß-unsaturated triazine esters as acyl electrophiles. Under base and phosphine ligand-free conditions, NHC-Pd(II)-Allyl precatalyst alone catalyzed the cross-coupling of α, ß-unsaturated triazine esters with terminal alkynes efficiently, yielding 31 cross-conjugated enynones with diverse functional groups. This method demonstrates the potential of triazine-mediated C-O activation for preparing highly functionalized ketones.

One-Dimensional Perovskite-like Cu(I)-Halides with Ideal Bandgap Based on Quantum-Well Structure.

Low-dimensional halide perovskites with quantum-well structures are promising materials for electronics and optoelectronics because of their excellent optoelectronic properties. This work concerns two novel, lead-free, one-dimensional organic-inorganic hybrid perovskite-like Cu(I) halides, (MV)Cu2X4 (MV = methyl viologen; X = Br, I), for optoelectronic applications. Both Cu(I) halides exhibited good stability under ambient conditions. The optical bandgaps of (MV)Cu2Br4 and (MV)Cu2I4 are 1.4 and 1.5 eV, respectively, which are in the ideal bandgap range for solar cells. (MV)Cu2Br4 possessed a characteristic quantum-well structure in which [CuBr4]n3n- chains with a nanowire-like structure were rolled up and isolated by tightly packed organic cations. Thanks to quantum confinement in the unique structure, the optical bandgap of (MV)Cu2Br4 fell in the ideal bandgap range for solar cells and was superior to that of (MV)Cu2I4. The good photoresponse properties of these Cu(I) halides suggest their great potential for application as light-harvesting materials in solar cells.

"On Water" Catalytic Aldol Reaction between Isatins and Acetophenones: Interfacial Hydrogen Bonding and Enamine Mechanism.

"On water" catalytic aldol reaction catalyzed by polyetheramine (D230) has been developed for easy access to 3-substituted 3-hydroxyindolin-2-ones through the reaction between various substituted isatins and acetophenones/cyclic ketones in high yields under room temperature. Systematic mechanism investigation uncovers the secret for the on water catalytic aldol reaction: comparison of the heterogeneous and homogeneous reaction circumstances with yields of 95 and 20%, respectively, indicates the on-water reaction dominating; interfacial hydrogen bonding between isatin with H2O is tested based on the downfield shift of the C2 and C3's 13C NMR signals when water was added to the CDCl3 solution of isatin; Lewis base polyetheramine D230 catalyzes the aldol reaction via the enamine mechanism verified by in situ NMR and ESI-MS analysis.

Indications of 5' to 3' Interbase Electron Transfer as the First Step of Pyrimidine Dimer Formation Probed by a Dinucleotide Analog.

Pyrimidine dimers are the most common DNA lesions generated under UV radiation. To reveal the molecular mechanisms behind their formation, it is of significance to reveal the roles of each pyrimidine residue. We thus replaced the 5'-pyrimidine residue with a photochemically inert xylene moiety (X). The electron-rich X can be readily oxidized but not reduced, defining the direction of interbase electron transfer (ET). Irradiation of the XpT dinucleotide under 254 nm UV light generates two major photoproducts: a pyrimidine (6-4) pyrimidone analog (6-4PP) and an analog of the so-called spore photoproduct (SP). Both products are formed by reaction at C4=O of the photo-excited 3'-thymidine (T), which indicates that excitation of a single "driver" residue is sufficient to trigger pyrimidine dimerization. Our quantum-chemical calculations demonstrated that photo-excited 3'-T accepts an electron from 5'-X. The resulting charge-separated radical pair lowers its energy upon formation of interbase covalent bonds, eventually yielding 6-4PP and SP.

Reactivity of damaged pyrimidines: formation of a Schiff base intermediate at the glycosidic bond of saturated dihydrouridine.

DNA glycosylases catalyze the first step of the base excision repair (BER) pathway. The chemistry used by these enzymes for deglycosylation has been largely considered as the chemistry of the oxocarbenium ion, e.g., direct rupture of the C1'-N1 bond resulting in an oxocarbenium ion intermediate. Here we present mechanistic studies revealing the 2'-deoxyribose isomerization and subsequent deglycosylation processes in two pyrimidine lesions: 5,6-dihydro-2'-deoxyuridine (dHdU) and 5,6-dihydrothymidine (dHT), formed via ionizing radiation damage to 2'-deoxycytidine and thymidine, respectively, under anoxic conditions. Acid or heat treatment of these two lesions leads to the production of two pairs of C1' epimers containing a pyranose and a furanose, respectively, indicating that both lesions favor the rupture of the C1'-O4' bond, resulting in a Schiff base intermediate at the N-glycosidic bond. Such a Schiff base intermediate was trapped and characterized by either Pd-catalyzed hydrogenation or thiol-mediated addition reaction. In contrast, in undamaged 2'-deoxyuridine and thymidine, reactions at elevated temperatures lead to the release of nucleobases most likely via the traditional oxocarbenium ion pathway. DFT calculations further support the experimental findings, suggesting that the oxocarbenium ion intermediate is responsible for the deglycosylation process if the integrity of the pyrimidine ring is maintained, while the Schiff base intermediate is preferred if the C5═C6 bond is saturated. Currently, the oxocarbenium ion pathway is indicated to be solely responsible for the deglycosylation in BER enzymes, however our results suggest an alternative Schiff base mechanism which may be responsible for the repair of saturated pyrimidine damages.

The structure of an authentic spore photoproduct lesion in DNA suggests a basis for recognition.

The spore photoproduct lesion (SP; 5-thymine-5,6-dihydrothymine) is the dominant photoproduct found in UV-irradiated spores of some bacteria such as Bacillus subtilis. Upon spore germination, this lesion is repaired in a light-independent manner by a specific repair enzyme: the spore photoproduct lyase (SP lyase). In this work, a host-guest approach in which the N-terminal fragment of Moloney murine leukemia virus reverse transcriptase (MMLV RT) serves as the host and DNA as the guest was used to determine the crystal structures of complexes including 16 bp oligonucleotides with and without the SP lesion at 2.14 and 1.72 Šresolution, respectively. In contrast to other types of thymine-thymine lesions, the SP lesion retains normal Watson-Crick hydrogen bonding to the adenine bases of the complementary strand, with shorter hydrogen bonds than found in the structure of the undamaged DNA. However, the lesion induces structural changes in the local conformation of what is otherwise B-form DNA. The region surrounding the lesion differs significantly in helical form from B-DNA, and the minor groove is widened by almost 3 Šcompared with that of the undamaged DNA. Thus, these unusual structural features associated with SP lesions may provide a basis for recognition by the SP lyase.

Reactivity of damaged pyrimidines: DNA cleavage via hemiaminal formation at the C4 positions of the saturated thymine of spore photoproduct and dihydrouridine.

Described here are mechanistic details of the chemical reactivities of two modified/saturated pyrimidine residues that represent naturally occurring forms of DNA damage: 5-thyminyl-5,6-dihydrothymine, commonly referred to as the "spore photoproduct" (SP), and 5,6-dihydro-2'-deoxyuridine (dHdU), formed via ionizing radiation damage to cytosine under anoxic conditions and also serving as a general model of saturated pyrimidine residues. It is shown that due to the loss of the pyrimidine C5-C6 double bond and consequent loss of ring aromaticity, the C4 position of both these saturated pyrimidines is prone to the formation of a hemiaminal intermediate via water addition. Water addition is facilitated by basic conditions; however, it also occurs at physiological pH at a slower rate. The hemiaminal species so-formed subsequently converts to a ring-opened hydrolysis product through cleavage of the pyrimidine N3-C4 bond. Further decomposition of this ring-opened product above physiological pH leads to DNA strand break formation. Taken together, these results suggest that once the aromaticity of a pyrimidine residue is lost, the C4 position becomes a "hot spot" for the formation of a tetrahedral intermediate, the decay of which triggers a cascade of elimination reactions that can under certain conditions convert a simple nucleobase modification into a DNA strand break.

Unusually large deuterium discrimination during spore photoproduct formation.

The deuterium-labeling strategy has been widely used and proved highly effective in mechanistic investigation of chemical and biochemical reactions. However, it is often hampered by the incomplete label transfer, which subsequently obscures the mechanistic conclusion. During the study of photoinduced generation of 5-thyminyl-5,6-dihydrothymine, which is commonly called the spore photoproduct (SP), the Cadet laboratory found an incomplete (~67%) deuterium transfer in SP formation, which contrasts to the exclusive transfer observed by the Li laboratory. Here, we investigated this discrepancy by re-examining the SP formation using d3-thymidine. We spiked the d3-thymidine with varying amounts of unlabeled thymidine before the SP photochemistry is performed. Strikingly, our data show that the reaction is highly sensitive to the trace protiated thymidine in the starting material. As many as 17-fold enrichment is detected in the formed SP, which may explain the previously observed one-third protium incorporation. Although commercially available deuterated reagents are generally satisfactory as mechanistic probes, our results argue that attention is still needed to the possible interference from the trace protiated impurity, especially when the reaction yield is low and large isotopic discrimination is involved.

Chemical syntheses of oligodeoxyribonucleotides containing spore photoproduct.

5-(α-Thyminyl)-5,6-dihydrothymine, also called spore photoproduct or SP, is commonly found in the genomic DNA of UV-irradiated bacterial endospores. Despite the fact that SP was discovered nearly 50 years ago, its biochemical impact is still largely unclear due to the difficulty of preparing SP-containing oligonucleotide in high purity. Here, we report the first synthesis of the phosphoramidite derivative of dinucleotide SP TpT, which enables successful incorporation of SP TpT into oligodeoxyribonucleotides with high efficiency via standard solid-phase synthesis. This result provides the scientific community a reliable means to prepare SP-containing oligonucleotides, laying the foundation for future SP biochemical studies. Thermal denaturation studies of the SP-containing oligonucleotide found that SP destabilizes the duplex by 10-20 kJ/mol, suggesting that its presence in the spore-genomic DNA may alter the DNA local conformation.

Palladium-catalysed Suzuki-Miyaura coupling of α,ß-unsaturated superactive triazine esters.

Palladium-catalysed Suzuki-Miyaura couplings of α,ß-unsaturated acid derivatives are challenging due to the susceptibility of their CC bonds adjacent to carbonyl groups. In this work, we describe a highly selective C-O activation approach to this transformation using superactive triazine esters and organoborons as coupling partners. 42 α,ß-unsaturated ketones with diverse functional groups have been prepared with this method. The mechanistic investigation unveiled that the dual function of triazine for activating the C-O bond and stabilizing non-covalent interactions between the catalyst and substrate is critical for the reaction's success. The method's efficiency, functional group compatibility and unique mechanism make it a valuable alternative to classic methods.

Mechanistic studies of the spore photoproduct lyase via a single cysteine mutation.

5-Thyminyl-5,6-dihydrothymine (also called spore photoproduct or SP) is the exclusive DNA photodamage product in bacterial endospores. It is repaired by a radical SAM (S-adenosylmethionine) enzyme, the spore photoproduct lyase (SPL), at the bacterial early germination phase. Our previous studies proved that SPL utilizes the 5'-dA• generated by the SAM cleavage reaction to abstract the H(6proR) atom to initiate the SP repair process. The resulting thymine allylic radical was suggested to take an H atom from an unknown protein source, most likely cysteine 141. Here we show that C141 can be readily alkylated in the native SPL by an iodoacetamide treatment, suggesting that it is accessible to the TpT radical. SP repair by the SPL C141A mutant yields TpTSO(2)(-) and TpT simultaneously from the very beginning of the reaction; no lag phase is observed for TpTSO(2)(-) formation. Should any other protein residue serve as the H donor, its presence would result in TpT being the major product at least for the first enzyme turnover. These observations provide strong evidence to support C141 as the direct H atom donor. Moreover, because of the lack of this intrinsic H donor, the C141A mutant produces TpT via an unprecedented thymine cation radical reduction (proton-coupled electron transfer) process, contrasting to the H atom transfer mechanism in the wild-type (WT) SPL reaction. The C141A mutant repairs SP at a rate that is ~3-fold slower than that of the WT enzyme. Formation of TpTSO(2)(-) and TpT exhibits a V(max) deuterium kinetic isotope effect (KIE) of 1.7 ± 0.2, which is smaller than the (D)V(max) KIE of 2.8 ± 0.3 determined for the WT SPL reaction. These findings suggest that removing the intrinsic H atom donor disturbs the rate-limiting process during enzyme catalysis. As expected, the prereduced C141A mutant supports only ~0.4 turnover, which is in sharp contrast to the >5 turnovers exhibited by the WT SPL reaction, suggesting that the enzyme catalytic cycle (SAM regeneration) is disrupted by this single mutation.

Synthesis of quinolines via sequential addition and I2-mediated desulfurative cyclization.

An efficient one-pot approach for the synthesis of quinolines from o-aminothiophenol and 1,3-ynone under mild conditions is disclosed. With the aid of ESI-MS analysis and parallel experiments, a three-step mechanism is proposed-a two-step Michael addition-cyclization condensation step leading to intermediate 1,5-benzothiazepine catalyzed by zirconocene amino acid complex Cp2Zr(η1-C9H10NO2)2, followed by I2-mediated desulfurative step.

One-step hydrothermal synthesis of chiral carbon dots with high asymmetric catalytic activity for an enantioselective direct aldol reaction.

Chiral carbon dots are prepared by a simple and one-step hydrothermal reaction at 180 °C for 2 h using citric acid and d-proline as precursors, which show high asymmetric catalytic activity for enantioselective direct aldol condensation. This work provides a hint for the simple preparation of heterogeneous chiral catalysts.

Synthesis of the structure proposed for the natural allenic antibiotic scorodonin.

The structure proposed for scorodonin, a natural allenyne with significant antibacterial and antifungal activities, was synthesized through an enantioselective route. The spectroscopic data of the synthetic allenyne are generally consistent with those reported for the natural one, but slight yet definite differences were observed in (13)C NMR.

The enantioselective total synthesis of nemotin.

The allene-diyne natural product nemotin was synthesized for the first time through an enantioselective route with the stereogenic center at the lactone moiety derived from l-glutamic acid and the allene axis constructed from the corresponding propargylic tosylate, and the absolute configuration was thus established as (4S,5aS).

Sustainable Ligand-Free, Palladium-Catalyzed Suzuki-Miyaura Reactions in Water: Insights into the Role of Base.

A simple and efficient system was developed for the ligand-free Pd-catalyzed Suzuki-Miyaura reaction in water under mild conditions. Quaternary ammonium hydroxides with long chains were found to be very suitable bases. This ligand-free Pd-catalyzed Suzuki-Miyaura reaction showed improved durability in water with Pd loadings decreased to ppm level. Bases were shown to stabilize active palladium species in addition to acting as a base during the catalytic process. In the catalytic system with a strong base, the soluble active PdII ion exhibited anti-reduction properties, which prevented aggregation and deactivation of Pd species. The entire catalytic system could be recycled after separating the product by simple filtration. The water-compatible and air-stable effective catalytic protocol described herein represents an attractive and green synthetic advance in Suzuki-Miyaura couplings.

N-Donor ligand activation of titanocene for the Biginelli reaction via the imine mechanism.

The remarkable activation of stable titanocene dichloride (Cp2TiCl2) was achieved using N-donor ligand urea in an alcoholic solvent, leading to the formation of a Ti(iv) species [(MeO)2Ti(NHCONH2)]+, the existence of which was verified by ESI-MS, ESI-MS/MS, and NMR. Catalyzed by the newly formed Ti(iv) species, a myriad of 3,4-dihydropyrimidin-2-(1H)-ones were produced via a three-component Biginelli reaction. Further mechanistic investigation indicated that the Biginelli reaction had taken place via the imine route.